Based on in vitro studies, it is widely believed that IL-2 and IL-4, T cell produced TCGFs, play an absolutely essential role in the execution of T cell mediated phenomena. Nonetheless, an exclusive role for these T-cell produced TCGFs in supporting the clonal proliferation and activation of effector of T cells during T cell dependent reactions in vivo, e.g. rejection, has not been established. We believe that IL-2 and IL-4 are not absolutely necessary for graft rejection as other "novel" TCGFs can also support the proliferation of antigen activated T-cells. Indeed, our studies of IL-2-/- single and IL-2-/-, IL-4-/- double gene knockout (DKO) islet cell allograft recipients indicate that other TCGFs can support vigorous islet allograft rejection. Insofar as IL-4 deficient mice do not produce IL-13, we believe that IL-7 and IL-15 (while not T-cell products) and IL-9 are potent TCGFs and are the most likely candidates for this role. We have detected greatly amplified IL-7 and IL-15 gene expression in acutely rejecting islet allografts of normal and IL-2-/- knockout recipients, as well as amplified gene expression in virtually all human renal allograft biopsies obtained from patients with acute rejection, but not other common causes of graft dysfunction (Strehlau et al., 1997). The possibility that expression of IL-7, IL-9 and IL-15 may play an important role in acute and chronic allograft rejection has received little attention. An understanding of the role of these TCGFs in allograft rejection is critically important in designing effective therapeutic strategies to promote long-term engraftment and tolerance. We will explore the role of these novel TCGFs and the therapeutic implications thereof during islet cell and cardiac allograft rejection by utilizing an IL-2 and IL-4-deficient system, the IL-2-/-, IL-4-/- DKO mouse, as well as normal mice as islet and cardiac allograft recipients.